{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T19:51:20Z","timestamp":1776455480508,"version":"3.51.2"},"reference-count":84,"publisher":"Oxford University Press (OUP)","issue":"48","license":[{"start":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T00:00:00Z","timestamp":1661472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Boehringer Ingelheim"},{"name":"Eli Lilly","award":["NCT03057977"],"award-info":[{"award-number":["NCT03057977"]}]},{"name":"Eli Lilly","award":["NCT03057951"],"award-info":[{"award-number":["NCT03057951"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink\u00ae Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by \u226510% with a false discovery rate &amp;lt;1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by \u226510% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehac495","type":"journal-article","created":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T09:28:52Z","timestamp":1661506132000},"page":"4991-5002","source":"Crossref","is-referenced-by-count":148,"title":["Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme"],"prefix":"10.1093","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-1570","authenticated-orcid":false,"given":"Faiez","family":"Zannad","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm, Centre d'Investigations Cliniques Plurith\u00e9matique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , 5, rue du Morvan, 54500 Vandoeuvre-Les-Nancy , France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2304-6138","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm, Centre d'Investigations Cliniques Plurith\u00e9matique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , 5, rue du Morvan, 54500 Vandoeuvre-Les-Nancy , France"},{"name":"Cardiovascular R&D Centre-UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto , Alameda Professor Hern\u00e2ni Monteiro 4200-319 Porto , Portugal"},{"name":"Internal Medicine Department, Centro Hospitalar de Vila Nova de Gaia\/Espinho, R. Concei\u00e7\u00e3o Fernandes S\/N , 4434-502 Vila Nova de Gaia , Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7683-4720","authenticated-orcid":false,"given":"Javed","family":"Butler","sequence":"additional","affiliation":[{"name":"Heart and Vascular Research, Baylor Scott and White Research Institute , 34 Live Oak St Ste 501, Dallas, TX 75204 , USA"},{"name":"University of Mississippi Medical Center , 2500 North State Street Jackson, MS 39216 , USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5640-0332","authenticated-orcid":false,"given":"Gerasimos","family":"Filippatos","sequence":"additional","affiliation":[{"name":"Heart Failure Unit, National and Kapodistrian University of Athens School of Medicine , Mikras Asias 75, Athina 115 27 Athens , Greece"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8338-1798","authenticated-orcid":false,"given":"James L","family":"Januzzi","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School , 55 Fruit St, Boston, MA 02114 USA"},{"name":"The Baim Institute for Clinical Research , 930 Commonwealth Ave #3, Boston, MA 02215 USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3827-5793","authenticated-orcid":false,"given":"Mikhail","family":"Sumin","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH , Binger Str. 173, 55218 Ingelheim am Rhein Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2508-4891","authenticated-orcid":false,"given":"Matthias","family":"Zwick","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG , Birkendorfer Str. 65, 88400 Biberach an der Riss Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9378-526X","authenticated-orcid":false,"given":"Maral","family":"Saadati","sequence":"additional","affiliation":[{"name":"Elderbrook Solutions GmbH on behalf of , Birkendorfer Str. 65, 88400 Biberach an der Riss , Germany"},{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG on behalf of , Birkendorfer Str. 65, 88400 Biberach an der Riss , Germany"}]},{"given":"Stuart J","family":"Pocock","sequence":"additional","affiliation":[{"name":"London School of Hygiene and Tropical Medicine , Keppel St, London WC1E 7HT UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-2593","authenticated-orcid":false,"given":"Naveed","family":"Sattar","sequence":"additional","affiliation":[{"name":"BHF, UK School of Cardiovascular and Metabolic Health, University of Glasgow , 126 University Place, Glasgow G12 8TA UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3331-7314","authenticated-orcid":false,"given":"Stefan D","family":"Anker","sequence":"additional","affiliation":[{"name":"Department of Cardiology (CVK) Berlin Institute of Health Center for Regenerative Therapies (BCRT) German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Charit\u00e9, Campus Virchow-Klinikum , Augustenburger Platz 1, D-13353 Berlin , 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